Tramadol HCl ER 100 mg Tablet, Extended Release, 60-count — NDC 61919-818-60 (Billing 61919-0818-60)

WARNINGS SECTION Seizure Risk Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous postmarketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking: Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or Other opioids.

Administration of tramadol may enhance the seizure risk in patients taking: MAO inhibitors (see also WARNINGS - Use with MAO Inhibitors ), Neuroleptics, or Other drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure.

Suicide Risk Do not prescribe tramadol hydrochloride extended-release tablets for patients who are suicidal or addiction-prone. Prescribe tramadol hydrochloride extended-release tablets with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess. Tell your patients not to exceed the recommended dose and to limit their intake of alcohol.

Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including tramadol hydrochloride extended-release tablets, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose. (See CLINICAL PHARMACOLOGY - Pharmacokinetics ).

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon.

Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics.

Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.

Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician.

Anaphylactoid Reactions Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS SECTION The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS (5.1)] Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS (5.3)] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see WARNINGS AND PRECAUTIONS (5.4)] Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS (5.5)] Interactions with Benzodiazepines or Other CNS Depressants [see WARNINGS AND PRECAUTIONS (5.7)] Serotonin Syndrome [see WARNINGS AND PRECAUTIONS (5.8)] Seizures [see WARNINGS AND PRECAUTIONS (5.9)] Suicide [see WARNINGS AND PRECAUTIONS (5.10)] Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS (5.11)] Severe Hypotension [see WARNINGS AND PRECAUTIONS (5.13)] Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS (5.15)] Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.16)] Withdrawal [see WARNINGS AND PRECAUTIONS (5.17)]

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tramadol hydrochloride was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older.

Table 1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to tramadol hydrochloride administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication.

The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride and the active control groups, TYLENOL with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol hydrochloride groups. Table 1: Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride in Chronic Trials of Nonmalignant Pain (N=427) Up to 7 Days Up to 30 Days Up to 90 Days Dizziness/Vertigo 26% 31% 33% Nausea 24% 34% 40% Constipation 24% 38% 46% Headache 18% 26% 32% Somnolence 16% 23% 25% Vomiting 9% 13% 17% Pruritus 8% 10% 11% “CNS Stimulation”1 7% 11% 14% Asthenia 6% 11% 12% Sweating 6% 7% 9% Dyspepsia 5% 9% 13% Dry Mouth 5% 9% 10% Diarrhea 5% 6% 10% 1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations Incidence 1% to Less than 5% Possibly Causally Related The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with tramadol hydrochloride exists.

Body as a Whole: Malaise. Cardiovascular: Vasodilation. Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal: Abdominal pain, Anorexia, Flatulence. Musculoskeletal: Hypertonia. Skin: Rash.

Special Senses: Visual disturbance. Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention. Incidence Less than 1%, Possibly Causally Related The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials of tramadol and/or reported in postmarketing experience with tramadol-containing products.

Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin synd… [Excerpted — this section continues on DailyMed.]

Table 2 includes clinically significant drug interactions with tramadol hydrochloride extended-release tablets. Inhibitors of CYP2D6 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.

Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)] .

Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.

Examples Quinidine, fluoxetine, paroxetine and bupropion Inhibitors of CYP3A4 Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)] , resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Intervention: If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.6)] .

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potenti… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS SECTION Acute Abdominal Condition The administration of tramadol hydrochloride extended-release tablets may complicate the clinical assessment of patients with acute abdominal conditions. Use in Renal and Hepatic Disease Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. Tramadol hydrochloride extended-release tablets have not been studied in patients with severe renal impairment (CLcr < 30 mL/min).

The limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release tablets do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, tramadol hydrochloride extended-release tablets should not be used in patients with severe renal impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver.

The pharmacokinetics of tramadol hydrochloride extended-release tablets has not been studied in patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release tablets do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, tramadol hydrochloride extended-release tablets should not be used in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

DRUG ABUSE AND DEPENDENCE SECTION Tramadol hydrochloride extended-release tablet is a mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion. Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm.

Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non- medical purposes, often in combination with other psychoactive substances.

Tramadol hydrochloride extended-release tablets, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Tramadol hydrochloride extended-release tablets are intended for oral use only. The crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances.

With parenteral abuse, the tablet excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Risk of Overdosage Serious potential consequences of overdosage with tramadol hydrochloride extended-release tablets are central nervous system depression, respiratory depression and death.

In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE ).